Total Synthesis of (+)-CC-1065 Utilizing Ring Expansion Reaction of

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Total Synthesis of (+)-CC-1065 Utilizing Ring Expansion Reaction of Benzocyclobutenone Oxime Sulfonate Taku Imaizumi, Yumi Yamashita,† Yuki Nakazawa,† Kentaro Okano, Juri Sakata, and Hidetoshi Tokuyama* Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan

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S Supporting Information *

ABSTRACT: An indole synthesis via ring expansion of benzocyclobutenone oxime sulfonate was developed. Utility of the indole synthesis was demonstrated by the total synthesis of (+)-CC-1065. The middle and right segments were constructed by a sequential ring expansion of the symmetrical benzo-bis-cyclobutenone. The left segment was also constructed via ring expansion of the methyl-substituted benzocyclobutenone oxime sulfonates. After condensation of these three segments, the dienone cyclopropane structure was formed to complete the total synthesis.

T

he compound (+)-CC-1065 (1), isolated from Streptomyces species by the Upjohn company in 1978, exhibits an extremely potent antitumor activity through irreversible formation of a covalent bond between its cyclopropa[c]pyrrolo[3,2-e]indol-4(5H)-one unit (2: CPI) and the DNA minor groove (Figure 1).1 Owing to this significant activity, related compounds possessing the DNA-alkylating structure of CPI (2) such as (+)-CC-1065 (1), yatakemycin (5), and

duocarmycins (6 and 7), as well as its DNA-binding moiety, that is, PDE−I (3) and PDE-II (4), have attracted considerable attention from the synthetic and medicinal communities. Since the work by Wierenga in 1981, a number of syntheses of CPI (2) and related compounds have been reported.2−6 Among them, the first total synthesis of (+)-CC1065 (1) reported in 19883 by Boger, along with extensive studies on its biological function including detailed structure− activity relationships and the development of artificial anticancer therapeutics, can be envisaged as the most important contributions in this area.7 In addition, Fukuyama and co-workers developed a practical strategy for the total syntheses of duocarmycins6a and (+)-yatakemycin (5)4b via a copper-mediated aryl amination reaction.8 In spite of the tremendous efforts made over the past few decades, the regioselective construction of highly or fully substituted pyrroloindoline structures contained in the above-mentioned compounds still constitutes a synthetic challenge. In this paper, we describe a novel indole synthesis that proceeds via ring expansion reaction of a benzocyclobutenone oxime sulfonate and its application to the total synthesis of (+)-CC-1065 (1). The retrosynthetic disconnection of two amide bonds of (+)-1 provides CPI (2) and two PDE segments 8 (Scheme 1). The latter would be derived from the pseudosymmetrical pyrroloindole 9. Because of steric and regiochemical reasons, construction of highly substituted pyrroloindoles such as 9 containing a fully substituted benzene ring is not an easy task. So far, several strategies have been developed to this aim,

Figure 1. (+)-CC-1065 (1) and related compounds.

Received: May 14, 2019

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.9b01690 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

We previously studied the DIBAL-mediated ring expansion of cyclic ketoximes in detail. For example, 1,2-reduction of benzocyclobutenone oxime 14 followed by a ring expansion and subsequent reduction of the resultant indolenine 15 provides indoline 16 (Scheme 2a).9 To apply this reaction to the synthesis of indoles or 2-substituted indoles, over reduction or a second nucleophilic addition to indolenine intermediate 18 must be prevented. In this regard, we reasoned that increase of the electrophilicity of oxime by a sulfonyl group would allow to conduct the reaction under milder reductant such as NaBH4 or cyanide nucleophiles. In addition, we expected the aromatization of 18 to give 19 would be faster than second nucleophilic addition to indolenine 18 (Scheme 2b).12,13 To test the working hypothesis, we prepared a series of oxime sulfonates (22), which were subjected to reductive conditions (Table 1).14 As expected, when 22a (R = Me) was treated with NaBH4 (10 equiv) in THF−MeOH at room temperature, the desired indole 23 was obtained in 13% yield along with 22a, and several kinds of byproducts including a trace amount of benzonitrile 24, which is most likely generated by Beckmann fragmentation via nucleophilic attack of hydride on the benzylic position (Table 1, entry 1). Then reactions of a series of p-substituted benzenesulfonates (22b−d) were examined (Table 1, entries 2−4). The yield of indole 23 was found to depend on the substituents on the benzene ring, with the chloro-substituted substrate 22c providing the best results. In the case of nitro-substituted substrate 22d, benzonitrile 24 was obtained as the major product (Table 1, entry 4). After further optimizations of the alcoholic co-solvents and reaction temperature (Table 1, entries 5−7), indole 23 was obtained in 71% yield by performing the reaction in THF/t-BuOH at 50 °C (Table 1, entry 7).15 We found that the oxime sulfonate was also applicable to the synthesis of 2-cyanoindole. Thus, treatment of 22c with KCN in THF/t-BuOH from rt to 60 °C afforded the desired 2cyanoindole 25 in low yield (Table 2, entry 1). The yield of 25 could be drastically improved by proper selection of solvent. Thus, reaction in DMSO or a mixture of DMSO/CH2Cl2 gave the desired 2-cyanoindole 25 in 89% or 95% yield, respectively (Table 2, entries 2 and 3). Since other cyanide sources, such as NaCN or Et4NCN, gave 2-cyanoindole 25 in slightly lower yields (Table 2, entries 4 and 5), we selected KCN as a choice of cyanide source. Having established the present novel indole synthesis, we then initiated the construction of the middle segment 38 and

Scheme 1. Retrosynthetic Analysis

including double C−N bond formation via nitrene species reported by Rees−Moody,5b and two distinct strategies via final formation of the fully substituted benzene ring from a bispyrrole precursor reported by Rawal−Cava5a and Magnus.5c We planned to construct the highly substituted pyrroloindole 9 through a two directional double ring expansion of benzo-biscyclobutenone oxime derivative 10 by improving a DIBALmediated oxime ring expansion (Scheme 2a).9 Accordingly, Scheme 2. Improvement of Ring Expansion Reaction

benzo-bis-cyclobutenone oxime 10 possessing a fully substituted benzene would be constructed via double [2 + 2] cycloaddition of 1,3-benzdiyne 13 with ketene dimethyl acetal 12.10,11

Table 1. Optimization of Hydride Mediated Ring Expansion Reaction of 22

entry

22

R

alcohol

temp

time (h)

23 (%)a

24 (%)a

1b 2c 3d 4e 5f 6e 7e

22a 22b 22c 22d 22c 22c 22c

Me p-MeC6H4 p-ClC6H4 p-NO2C6H4 p-ClC6H4 p-ClC6H4 p-ClC6H4

MeOH MeOH MeOH MeOH MeOH i-PrOH t-BuOH

rt rt rt rt 50 °C 50 °C 50 °C

24 24 24 1 24 20 7

13 11 25 6 30 46 71

trace trace trace 60 trace 2 trace

a

Isolated yield. b22a (28%) was recovered. c22b (59%) was recovered. d22c (21%) was recovered. e22 was completely consumed. f22c (12%) was recovered. B

DOI: 10.1021/acs.orglett.9b01690 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

double ring expansion. Thus, initial treatment of 29 with KCN afforded only a trace amount of indole along with unidentified byproducts. On the other hand, the initial use of NaBH4 gave indole 30 in 60% yield.18 After isolation, 30 was then treated with KCN to promote the second ring expansion, which afforded the desymmetrized pyrroloindole 9 in 73% yield. Since the standard acidic or basic hydrolysis conditions resulted in decomposition, the cyano group was converted to carboxylic acid by a stepwise manner.19 Accordingly, DIBAL reduction of 9 followed by Boc protection and Pinnick oxidation gave carboxylic acid 32. After methylation of the carboxylic acid and removal of the Boc group, the resultant compound 33 was converted to PDE−I (3) by following reported procedures.5h On the other hand, carboxylic acid 32 was converted to the middle segment 38 by a sequence including condensation with benzylalcohol, removal of the Boc group, and reduction of a pyrrole ring with NaBH3CN in acetic acid to give pyrroloindoline 35. After installation of the Fmoc group, an Fmoc-directed regioselective demethylation with BCl3 was carried out to obtain phenol 37. Finally, reductive cleavage of the Bn group gave the middle segment 38. The CPI (2) segment was also synthesized using the newly developed ring expansion reaction of oxime sulfonate as the key process. On the basis of our total synthesis of (+)-yatakemycin (5),4b in which the dienone cyclopropane structure was formed at the late stage via ring contraction, we selected pyrrolotetrahydroquinoline 47 as the precursor of CPI (2) (Scheme 4). The synthesis of 47 commenced with the

Table 2. Optimization of Cyanide Sources

entry

nucleophiles

solvents

temp

time (h)

25 (%)a

1b 2 3c 4c 5c

KCN KCN KCN NaCN Et4NCN

THF/t-BuOH DMSO DMSO/CH2Cl2 DMSO/CH2Cl2 DMSO/CH2Cl2

rt to 60 °C rt 0 °C 0 °C 0 °C

24 1 1 0.4 0.25

8 89 95 93 82

a

Isolated yield. bReaction performed in THF and t-BuOH (4:1). Reaction performed in DMSO and CH2Cl2 (3:1).

c

PDE−I (3) via the planned two directional double ring expansion strategy (Schemes 3). Dibromoveratrole 26,16 a Scheme 3. Synthesis of PDE-I (3) and Middle Segment 38a

Scheme 4. Synthesis of Pyrrolotetrahydroquinoline 47a

a

Reagents and conditions: (a) 12, NaNH2, THF, reflux, 89%; (b) 6 M aq. HCl, acetone/CHCl3; (c) NH2OH·HCl, pyridine, 70 °C; (d) p-ClC6H4SO2Cl, Et3N, CH2Cl2, 53% (3 steps from 27, single isomer); (e) NaBH4, THF/t-BuOH, 50 °C, 60%; (f) KCN, DMSO/CH2Cl2, 0 °C, 73%; (g) DIBALH, toluene, −78 °C, 63%; (h) Boc2O, DMAP, MeCN; (i) NaClO2, NaH2PO4, 2-methyl-2-butene, THF/t-BuOH/ H2O; (j) MeI, NaHCO3, DMF; (k) o-dichlorobenzene, 185 °C, 80% (4 steps from 31); (l) BnOH, DCC, DMAP, CH2Cl2; (m) odichlorobenzene, 185 °C, 80% (4 steps from 31); (n) NaBH3CN, AcOH; (o) FmocCl, NaHCO3, THF/H2O, 82% (2 steps from 34); (p) BCl3, CH2Cl2, 0 °C, 67%; (q) H2, Pd/C, EtOAc/EtOH, quant.

a

Reagents and conditions: (a) n-Bu3P, THF; H2O; Boc2O, 91%; (b) LiTMP, THF, −78 °C, 61%; (c) 42, LiTMP, THF, −78 °C; (d) AcOH, THF/H2O; (e) NH2OH·HCl, pyridine, 70 °C, 54%, (3 steps from 41, dr = 1:1); (f) p-ClC6H4SO2Cl, Et3N, CH2Cl2, 91%; (g) NaBH4, DMSO/t-BuOH, 70 °C, 76%; (h) TMSI, CH2Cl2, 0 °C, 96%.

Staudinger reaction of optically active azide 39,4b and subsequent Boc protection of the resulting primary amine afforded carbamate 40. The tetrahydroquinoline ring in 41 was formed by benzyne-mediated amino cyclization of N-Boc carbamate 40 by treatment with LiTMP.20 Then the completely regioselective [2 + 2] cycloaddition of ketene silyl acetal 4221 with a benzyne intermediate generated from 41 produced adduct 43.18 After acid hydrolysis of the acetal, the resultant ketone was converted to oxime sulfonate 45, which was then subjected to the crucial ring expansion reaction. However, the optimal conditions did not afford indole 46 in sufficient yield (43%). Fortunately, extensive

synthetic equivalent of 1,3-benzdiyne 13,11 was treated with NaNH2 in the presence of ketene dimethyl acetal 1210 to give tricyclic diacetal 27 with complete regioselectivity,17 which was then converted to symmetrical bis-oxime sulfonate 29 via successive hydrolysis of dimethyl acetal, oximation, and sulfonylation (Scheme 3). At this point, we found that the order of indole formation and 2-cyanoindole formation was crucial for desymmetrization of bis-oxime sulfonate 29 via C

DOI: 10.1021/acs.orglett.9b01690 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Notes

optimizations revealed that the use of a combination of DMSO and t-BuOH as solvent at 70 °C improved the yield up to 76%. Finally, removal of the Boc group by TMSI gave the left segment 47.22 The remaining tasks to complete the total synthesis were coupling of each segment and construction of the cyclopropane moiety (Scheme 5). Condensation of the segments 47

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by KAKENHI (JP16H01127, JP16H00999, JP26253001, JP18H02549, JP18H04231, JP18H04379, JP18K18462) and Platform Project for Supporting Drug Discovery and Life Science Research (BINDS) from AMED under Grant No. JP18am0101100.

Scheme 5. Completion of Total Synthesisa

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a

Reagents and conditions: (a) WSCD·HCl, THF, 91%; (b) TBAF, THF; 3, WSCD·HCl, HOBt, DMF, 63%; (c) TBAF, THF; evaporation; MsCl, pyridine, 84%; (d) H2, Pd(OH)2/C, THF; Et3N, 34%.

and 38 using WSCD·HCl in DMF gave 48 in good yield. Then careful deprotection of the Fmoc group with TBAF, followed by one-pot condensation with PDE−I (3), furnished 49. After the TBS group was replaced with Ms, hydrogenolytic cleavage of the Bn group with catalytic Pd(OH)2, and treatment of the resulting phenol with Et3N for the transannular cyclopropanation furnished (+)-CC-1065 (1), which was identical in all respects to the natural product.3b In conclusion, we have achieved the total synthesis of (+)-CC-1065 (1). The key synthetic feature of our synthesis was the novel indole synthesis utilizing a ring expansion reaction of benzocyclobutenone oxime sulfonate, which effectively contributed to the construction of the highly functionalized pyrroloindoline segments. Further studies on this indole synthesis including detailed mechanistic investigation, scope, and limitations are now ongoing in our laboratory.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01690. Full experimental procedure, characterization data and copies of NMR spectra for all new compounds (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Kentaro Okano: 0000-0003-2029-8505 Hidetoshi Tokuyama: 0000-0002-6519-7727 Author Contributions †

Y.Y. and Y.N. contributed equally to this work. D

DOI: 10.1021/acs.orglett.9b01690 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters 69, 7190−7197. (c) Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.; Osamura, Y.; Suzuki, K. Org. Lett. 2003, 5, 3551−3554. (12) Ring expansion reaction of O-sulfonyl hydroxylamine, see: Hoffman, R. V.; Buntain, G. A. J. Org. Chem. 1988, 53, 3316−3321. (13) Ring expansion of benzocyclubutenone oxime ether with Grignard reagent, see: Nishida, Y.; Ueda, M.; Hayashi, M.; Takeda, N.; Miyata, O. Eur. J. Org. Chem. 2016, 2016, 22−25. (14) For the preparation of 22, see Supporting Information. (15) We have no clear explanation of this drastic improvement. We consider observed solvent effects would be attributed from the varied solubility, and reactivity of NaBH4 or its alkoxy substituted derivatives. For examples, see: (a) Ward, D. E.; Rhee, C. K. Can. J. Chem. 1989, 67, 1206−1211. (b) Soai, K.; Oyamada, H.; Ookawa, A. Synth. Commun. 1982, 12, 463−467. (16) Reynes, M.; Dautel, O. J.; Virieux, D.; Flot, D.; Moreau, J. J. E. CrystEngComm 2011, 13, 6050−6056. (17) For the high regioselectivity, see: Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 1995, 36, 3377−3880. (18) This excellent chemoselectivity should be explained by the relatively lower electrophilicity of the remaining oxime sulfonate in 30 due to the electron donating effect of electron rich pyrrole ring compared to that of the bis-oxime sulfonate 29. (19) For details, see Supporting Information. (20) Oshiyama, T.; Satoh, T.; Okano, K.; Tokuyama, H. Tetrahedron 2012, 68, 9376−9383. (21) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki, K. Synlett 1995, 2, 177−179. (22) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. J. Chem. Soc., Chem. Commun. 1979, 495−496.

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DOI: 10.1021/acs.orglett.9b01690 Org. Lett. XXXX, XXX, XXX−XXX